An alternative process for the synthesis of 6-alpha-(aminomethyl)penicillanic acid and its derivatives is described. This process proceeds stereospecifically from 6-alpha-bromopenicillanate 1,1-dioxide esters, via the corresponding 6-alpha-bromomagnesium Grignard reagent and the 6-alpha(benzyloxycarbonylaminomethyl) derivative. This synthesis is of particular value in the preparation of diastereomeric R- and S-1-(ethoxycarbonyloxy)ethyl 6-alpha-(aminomethyl)penicillanate 1,1-dioxide.
My co-pending U.S. patent application Ser. No. 434,371, filed Oct. 21, 1982 now U.S. Pat. No. 4,452,796 describes alternative processes for 6-alpha-(aminomethyl)penicillanic acid 1,1-dioxide, salts thereof, and certain esters thereof which are hydrolyzable under physiological conditions; and further describes the antibacterial utility of these compounds, principally as beta-lactamase inhibitors useful in combination with conventional beta-lactam antibiotics.
The present process is particularly advantageous in the synthesis of R- and S-1-(ethoxycarbonyloxy)ethyl 6-alpha-(aminomethyl)penicillanate 1,1-dioxide. Although in my above cited earlier application, I have generally described 1-(ethoxycarbonyloxy)ethyl esters, I did not describe the present, highly valuable R- and S-diastereoisomers, which are now efficiently available by the present novel process.
Other compounds previously reported as beta-lactamase inhibitors useful in combination with beta-lactam antibiotics for the treatment of bacterial infections include penicillanic acid 1,1-dioxide and esters thereof readily hydrolyzable in vivo (Barth, U.S. Pat. No. 4,234,579); the bis-methanediol ester of sulbactam (Bigham, U.S. Pat. No. 4,309,347); various 6-beta-(hydroxymethyl)penicillanic acid 1,1-dioxides and esters thereof (Kellogg, U.S. Pat. No. 4,287,181); and 6-beta-(aminomethyl)penicillanic acid (McCombie, U.S. Pat. No. 4,237,051).
U.K. Patent Application No. 2,053,220, published Feb. 4, 1981, broadly discloses beta-lactamase inhibiting compounds of the formula ##STR1## The definitions of R.sub.a, R.sub.b and R.sub.c define literally an infinite number of compounds. These definitions, by appropriate selection of R.sub.a, R.sub.b and R.sub.c, may possibly define the 6-alpha-(aminomethyl)penicillanic acid 1,1-dioxides of present interest. No specific method for preparation of these compounds is present in the disclosure of this U.K. application, and there is no hint or suggestion that from among the infinity of compounds proposed, the present aminomethyl compounds are preferred compounds, possessing the particularly highly potent beta-lactamase inhibitory activity which we have determined for them.
DiNinno et al., J. Org. Chem. 42, pages 2960-2965 (1977) [see also Beattie et al., U.S. Pat. No. 4,207,323 (1980)] have previously described structurally related Grignard reagents derived from 6-alpha-bromopenicillanates (reacted with acetaldehyde), likewise formed at low temperatures. The present Grignard reagents derived from 6-alpha-bromopenicillanate 1,1-dioxides are distinguished thereover by the surprising fact that it has been found possible to retain 6-alpha-stereochemistry in the derived Grignard reagent.
Concurrently filed U.S. patent application Ser. No. 501,475 for "beta-Lactamase Inhibiting 6-(Alkoxyaminomethyl)penicillanic Acid 1,1-Dioxide and Derivatives" by D. K. Pirie et al. discloses a further useful process for 6-alpha-(aminomethyl)penicillanic acid 1,1-dioxide and derivatives, which proceeds via the present, sterically stable Grignard reagents derived from 6-alpha-bromopenicillanate ester 1,1-dioxides.